Patients with critical surgical disorders such as trauma, thermal injury, shock, sepsis, and massive surgical operations are commonly complicated with acute gut mucosal injury and bleeding. Disruption of the gut epithelial integrity causes sepsis and in some instances acts as the trigger that drives multiple organ dysfunction syndrome (MODS), a leading cause of death in critically ill patients. Effective therapies to enhance mucosal defense and promote epithelial repair after acute injury in patients with critical surgical illnesses are limited, contributing to massive mucosal hemorrhage, impaired repair, and gut barrier dysfunction. During the previous funding periods, we have demonstrated that protein phosphatase 2A (PP2A)-associated protein ?4 plays an important role in intestinal mucosal regeneration and defense, but its exact mechanism underlying ?4-regulated intestinal homeostasis remains largely unknown. Noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long ncRNAs (lncRNAs), have recently emerged as a novel class of master regulators of the intestinal epithelium homeostasis and are also implicated in different human diseases. miRNAs and lncRNAs modulate expression of target genes and thus regulate a variety of cellular processes. Our preliminary results indicate that a) targeted deletion of ?4 in mice decreased the levels of mucosal miR-503 and lncRNA uc.230 in the intestine; b) specific inhibition of miR-503 and uc.230 by transfection with their antagonisms repressed intestinal epithelial repair after wounding and also enhanced epithelial cell apoptosis; and c) miR-503 inhibited expression of antizyme (AZ; a negative regulator of polyamine biosynthesis), whereas uc.230 up-regulated Rac1 and inhibitor of apoptosis protein 1 (IAP1). Based on these exciting observations, we HYPOTHESIZE that ?4 promotes intestinal epithelial homeostasis by modulating miRNA miR- 503 and lncRNA uc.230 in critical surgical conditions. Three specific aims are proposed to test the hypothesis: 1) to examine the expression profiles of miRNAs and lncRNAs in the ?4-deficient intestinal epithelium in response to surgical stress; 2) to determine the exact roles of miR-503 and uc.230 in ?4-regulated mucosal repair and apoptosis; and 3) to define the mechanisms by which miR-503 and uc.230 regulate expression of AZ, Rac1, and IAP1. Completion of these specific aims will make a conceptual advance by linking ?4/ncRNA pathway with gut epithelium homeostasis under critical surgical conditions. These studies will also create a fundamental basis for development of novel therapies to preserve epithelial integrity in our VA patients, thus decreasing morbidity and mortality of massive mucosal injury and inflammation, delayed repair, sepsis, and MODS by targeting ?4 and its regulatory ncRNAs.